Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An X-linked severe combined immunodeficient (SCID) patient received a nonirradiated erythrocyte transfusion and developed transfusion-associated graft-versus-host disease (TAGVHD), which was controllable with high-dose corticosteroids. Haplo-identical SCT was performed, after a myeloablative conditioning regimen. At day +26, he developed GVHD. Chimerism studies revealed DNA of the erythrocyte transfusion donor (ETD) and recipient only. Because of early nonengraftment and the presence of alloreactive T cells of ETD origin, the patient was treated with an immunosuppressive conditioning regimen followed by a second SCT from the same donor. While tapering immunosuppression, he again developed mild GVHD, and DNA of ETD and bone marrow donor origin were both present. On cyclosporin, the ETD-DNA signal finally disappeared. High-resolution HLA typing revealed haplo-identity between BMD, ETD and the patient, which might have contributed to the relative mild course of the TAGVHD.
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PMID:Nonlethal transfusion associated graft-versus-host disease in a severe combined immunodeficient patient. 1459 91

Mutations in nine different genes have been found to cause the human severe combined immunodeficiency syndrome. The products of three of the genes--IL-2RG, Jak3, and IL-7R alpha--are components of cytokine receptors, and the products of three more-RAG1, RAG2, and Artemis-are essential for effecting antigen receptor gene rearrangement. Additionally, a deficiency of CD3 delta, a component of the T-cell antigen receptor, results in a near absence of circulating mature CD3+ T cells and a complete lack of gamma/delta T cells. Adenosine deaminase deficiency results in toxic accumulations of metabolites that cause T cell apoptosis. Finally, a deficiency of CD45, a critical regulator of signaling thresholds in immune cells, also causes SCID. Approaches to immune reconstitution have included bone marrow transplantation and gene therapy. Bone marrow transplantation, both HLA identical unfractionated and T cell-depleted HLA haploidentical, has been very successful in effecting immune reconstitution if done in the first 3.5 months of life and without pretransplant chemotherapy. Gene therapy was highly successful in nine infants with X-linked SCID, but the trials have been placed on hold due to the development of a leukemic process in two of the children because of insertional oncogenesis.
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PMID:Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. 1503 91

IPEX syndrome is a genetic autoimmune disease characterized by immune-mediated polyendocrinopathy, enteropathy, and X-linked inheritance. We describe a case of IPEX in which lymphocyte phenotypes were assessed at birth, before initiation of Cyclosporin A therapy, and at frequent intervals to 18 months of age. We performed flow cytometry for lymphocyte subtypes and for activation markers (HLA-DR, CD25, and CD69 or CD71). The ratios of both T to B cells and CD4+ to CD8+ cells were elevated at birth, but CD4+ cells were not activated. HLA-DR+ and CD25+ activated T-cells increased in association with two episodes of clinical deterioration: colitis and the onset of type I diabetes mellitus. These results indicate that measures of activation, particularly HLA-DR+ and CD25+ frequency, correlate well with the development of early active disease and may presage clinical episodes. Continuous maintenance of immunosuppression, once started, appears critical for prevention of permanent tissue damage.
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PMID:Prospective immunological profiling in a case of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX). 1527 Aug 55

Preimplantation genetic diagnosis (PGD) has recently been offered in combination with HLA typing, which allowed a successful haematopoietic reconstitution in affected siblings with Fanconi anaemia by transplantation of stem cells obtained from the HLA-matched offspring resulting from PGD. This study presents the results of the first PGD practical experience performed in a group of couples at risk for producing children with genetic disorders. These parents also requested preimplantation HLA typing for treating the affected children in the family, who required HLA-matched stem cell transplantation. Using a standard IVF procedure, oocytes or embryos were tested for causative gene mutations simultaneously with HLA alleles, selecting and transferring only those unaffected embryos, which were HLA matched to the affected siblings. The procedure was performed for patients with children affected by Fanconi anaemia (FANC) A and C, different thalassaemia mutations, Wiscott-Aldrich syndrome, X-linked adrenoleukodystrophy, X-linked hyperimmunoglobulin M syndrome and X-linked hypohidrotic ectodermal displasia with immune deficiency. Overall, 46 PGD cycles were performed for 26 couples, resulting in selection and transfer of 50 unaffected HLA-matched embryos in 33 cycles, yielding six HLA-matched clinical pregnancies and the birth of five unaffected HLA-matched children. Despite the controversy of PGD use for HLA typing, the data demonstrate the usefulness of this approach for at-risk couples, not only to avoid the birth of affected children with an inherited disease, but also for having unaffected children who may also be potential HLA-matched donors of stem cells for treatment of affected siblings.
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PMID:Preimplantation genetic diagnosis with HLA matching. 1533 54

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency with a median survival below the age of 20 due to infections, severe hemorrhage, and lymphomas. Transplantation of hematopoietic stem cells from HLA-identical sibling donors is a resolutive treatment, but is available for a minority of patients. Transplantation of genetically corrected autologous hematopoietic stem cells or T cells could represent an alternative treatment applicable to all patients. We investigated whether WAS gene transfer with MMLV-based oncoretroviral and HIV-based lentiviral vectors could restore normal functions of patients' T cells. T cells transduced either with lentiviral vectors expressing the WAS protein (WASP) from the ubiquitous PGK promoter or the tissue-specific WASP promoter or with an oncoretroviral vector expressing WASP from the LTR, reached normal levels of WASP with correction of functional defects, including proliferation, IL-2 production, and lipid raft upregulation. Lentiviral vectors transduced T cells from WAS patients at higher rates, compared to oncoretroviral vectors, and efficiently transduced both activated and naive WAS T cells. Furthermore, a selective growth advantage of T cells corrected with the lentiviral vectors was demonstrated. The observation that lentiviral vector-mediated gene transfer results in correction of T cell defects in vitro supports their application for gene therapy in WAS patients.
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PMID:Lentiviral vector-mediated gene transfer in T cells from Wiskott-Aldrich syndrome patients leads to functional correction. 1550 8

Since the early 1990s, preimplantation genetic diagnosis (PGD) has been expanding in scope and applications. Selection of female embryos to avoid X-linked disease was carried out first by polymerase chain reaction, then by fluorescence in situ hybridization (FISH), and an ever-increasing number of tests for monogenic diseases have been developed. Couples with chromosome rearrangements such as Robertsonian and reciprocal translocations form a large referral group for most PGD centers and present a special challenge, due to the large number of genetically unbalanced embryos generated by meiotic segregation. Early protocols used blastomeres biopsied from cleavage-stage embryos; testing of first and second polar bodies is now a routine alternative, and blastocyst biopsy can also be used. More recently, the technology has been harnessed to provide PGD-AS, or aneuploidy screening. FISH probes specific for chromosomes commonly found to be aneuploid in early pregnancy loss are used to test blastomeres for aneuploidy, with the aim of replacing euploid embryos and increasing pregnancy rates in groups of women who have poor IVF success rates. More recent application of PGD to areas such as HLA typing and social sex selection have stoked public controversy and concern, while provoking interesting ethical debates and keeping PGD firmly in the public eye.
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PMID:Preimplantation genetic diagnosis--an overview. 1574 97

We retrospectively analyzed our results of 30 patients with three distinctive primary immunodeficiency diseases (PIDs)--severe combined immunodeficiency (SCID, n = 11), Wiskott-Aldrich syndrome (WAS, n = 11) and X-linked hyper-immunoglobulin M (IgM) syndrome (XHIM, n = 8)--who underwent hematopoietic SCT (HSCT) during the past 20 years. Until 1995, all donors were HLA-haploidentical relatives with T-cell depletion (TCD) (n = 8). Since 1996, the donors have been HLA-matched related donors (MRD) (n = 8), unrelated BM (UR-BM) (n = 7) and unrelated cord blood (UR-CB) (n = 7). Twenty-seven of 30 patients had various pre-existing infections with or without organ damages before HSCT. Conditioning regimen and GVHD prophylaxis were determined according to disease, donor and pretransplant status. Although one of eight patients transplanted with TCD is alive with full engraftment, the other seven died. On the other hand, 18 of 22 patients transplanted without TCD are alive and well, including six of eight transplanted from MRD, seven of seven from UR-BM and five of seven from UR-CB. All 19 survivors did not require Ig supplementation after HSCT. These results indicate that UR-CBT as well as UR-BMT provides good results for PID comparable to MRD-SCT, and that early diagnosis, HSCT at early stage, careful supportive therapy and monitoring for various pathogens are important for the successful HSCT.
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PMID:Hematopoietic stem cell transplantation for 30 patients with primary immunodeficiency diseases: 20 years experience of a single team. 1643 16

We report serial transplantation procedures in 2 sets of brothers with X-linked primary immunodeficiency. The first boy in each family received a T-cell-depleted transplant from a mismatched donor. The recipients then acted as donors for T-replete transplantation of the "tolerized" graft into their HLA-identical brothers with the same disorder. Immune reconstitution was noted to occur at a significantly faster rate in the secondary recipients, and without the occurrence of graft-versus-host disease (GVHD), despite the presence of donor cells mismatched for 1 to 3 HLA antigens. This serial transplantation technique allows the primary recipient of HLA-mismatched donor cells to act as a functionally "HLA-matched" donor for subsequent affected siblings, and should be considered as a therapeutic option in families with congenital disorders.
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PMID:Serial transplantation of mismatched donor hematopoietic cells between HLA-identical sibling pairs with congenital immunodeficiency: in vivo tolerance permits rapid immune reconstitution following T-replete transplantation without GVHD in the secondary recipient. 1672 99

Graft rejection has long been considered the paradigm of renal diseases induced by alloimmunization, particularly alloimmunization directed against HLA antigens. Accumulating evidence indicates that non-HLA immunity also has an important role in clinical transplantation. Targets of alloimmunization include antigens of tubular basement membrane, tubular epithelial cells and endothelial cells. They can be polymorphic allovariants (as shown in the rat) or 'hidden' antigens exposed when the graft is damaged. Alloimmunization can also occur when a person genetically deficient in a renal protein (e.g. the alpha5 (IV) collagen chain in X-linked Alport's syndrome or nephrin in Finnish-type nephrotic syndrome) is transplanted to treat end-stage renal failure. The non-mutated protein in the donor kidney is recognized as a foreign antigen, and the resulting alloimmune response can damage the graft. We have demonstrated that alloimmunity can also affect the native kidney. We have characterized a novel fetomaternal disease in which a genetic defect in the MME gene encoding neutral endopeptidase (NEP) in the mother leads to the development of membranous nephropathy in her fetus (maternal anti-NEP antibodies bind to NEP on fetal podocytes). Our findings raise the possibility that mutations or genetic polyporphisms in MME or other genes expressed by the podocyte are involved in alloimmune-mediated development of membranous nephropathy after kidney or bone marrow transplantation.
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PMID:Mechanisms of disease: Alloimmunization in renal diseases. 1693 67

In all caucasian populations the association of an impressive number of autoimmune diseases with genes from the HLA-B8, DR3 haplotype that is part of the ancestral haplotype (AH) 8.1 HLA-A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*0301, DRB3*0101, DQA1*0501, DQB1*0201 has been reported by different research groups. This haplotype, which is more common in northern Europe, is also associated with a number of immune system dysfunctions in healthy subjects. Analyzing the data according to gender, some dysfunctions are observed in women but not in men, in agreement with the role of X-linked genes and/or estrogens in the development and progression of autoimmune diseases. It has been proposed that a small number of genes within the 8.1 AH modify immune responsiveness and hence affect multiple immunopathological diseases. In this article, we demonstrate that neutrophil chemotaxis is significantly decreased in carriers of this AH, suggesting that this impairment may also be related to the increased occurrence of autoimmune diseases in these individuals.
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PMID:Genetic control of immune response in carriers of ancestral haplotype 8.1: the study of chemotaxis. 1726 94


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